Bacteria have evolved regulatory mechanisms to maintain iron homeostasis to prevent excess intake of reactive iron. However, during symbiosis between the soil bacterium Sinorhizhobium meliloti and the leguminous plant Medicago truncatula, the highly iron requiring process of nitrogen fixation is carried out by the bacterium, thus creating an unusually high demand for iron. An arsenal of 600 defensin-like “nodule-specific cysteine-rich” (NCR) peptides are produced by M. truncatula, to manipulate the life cycle of S. meliloti. Here, I show that NCR247, a 24-amino acid NCR peptide, enters S. meliloti, binds intracellular heme with drug-like affinity (KD of 1 nM) and sequesters it, first into hexamers and then into higher-order complexes. This allows the iron response regulator (Irr), a transcriptional regulator whose DNA-binding decreases upon heme binding, to be unusually stable and activate iron import even under iron-replete conditions. Thus, NCR247 overrides the bacterial regulation of iron homeostasis and tricks the bacterium into importing higher amounts of iron, in order to aid in nitrogen fixation. I show that NCR247 binds ferric heme to generate a hyper porphyrin spectrum, and the six-coordinate, low spin heme iron in the complex is double cysteine ligated. Clinically relevant biochemical properties of NCR247-heme interaction include i) The protease-resistant D enantiomeric NCR247 binds heme with the same affinity; ii) NCR247 binding renders heme unreactive; and, iii) The water-soluble NCR247 is cheap and easy to synthesize chemically. Exploiting this, I have developed a variety of potential clinical applications including inhibiting the growth of serious heme-requiring pathogens (H. influenzae and P. gingivalis) and parasites (T. gondii), preventing the formation of Candida biofilms, preventing the toxic peroxidase activity of Aβ-heme complex associated with Alzheimer’s disease and removing toxic free heme accumulated in stored blood.

Heme-sequestering host plant peptide drives iron uptake in symbiotic bacteria: Significance and potential clinical applications

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